Obesity, a source of significant morbidity and increased mortality of the U.S. population, is among major public health problems in the country. Today's epidemic of obesity and associated disorders shows no signs of slowing down and threatens to undo the improvements in American health statistics achieved by reductions in cardiovascular morbidity. See Yach, D., et al., Nat. Med., 12: 62-66 (2006). Needless to say, the benefits from losing weight are both medical and cosmetic, and since the majority of obese patients are excellent candidates for pharmacological treatments, the “race is on for the pill to control obesity”. See Yach, D., et al., Nat. Med., 12: 62-66 (2006). Despite these many efforts and a critical demand for safe and effective agents, there are only few agents currently approved by the FDA and available for clinical use in obese patients. See Bray, G. A., et al., Pharmacol. Rev., 59: 151-184 (2007).
Considerable evidence exists that an increase in sugar consumption and drinking of sweetened substances can lead to obesity in humans. See Bray, G. A., et al., Am. J. Clin. Nutr., 79: 537-543 (2004) and Bray, G. A., et al., Am. J. Clin. Nutr., 55: 151 S-154S (1992). Thus, several animals models based on consumption of palatable fluids were developed to assess different aspects of excessive eating behavior and obesity. See Speakman, J., et al., Obes. Rev., 8 Suppl 1: 55-61 (2007). For example, intermittent sugar intake models have been applied to study compulsive bingeing behavior (see Avena, N. M., et al., Neurosci. Biobehav. Rev., (2007)), while continuous sugar intake models have been used to assess body weight dynamics and its hormonal regulation (see Bock, B. C., et al., Physiol Behav., 57: 659-668 (1995)). Furthermore, operant administration of sucrose and other sweet solutions has been previously utilized to assess appetitive and motivational aspects of aberrant eating behavior. See Sclafani, A., Physiol Behav., 87: 734-744 (2006) and Sclafani, A., et al., Physiol Behav., 79: 663-670 (2003).
Mesolimbic dopamine is critically involved in mediation of food reward (see Berridge, K. C., Neurosci. Biobehav. Rev., 20:1-25 (1996)), satiety and expression of ingestive motor behavior. See Berthoud, H. R., Neurosci. Biobehav. Rev., 26: 393-428 (2002). Ingestion of sucrose or saccharine were shown to increases dopamine release in the nucleus accumbens (see Glick, S. D., et al., Eur. J. Pharmacol., 537: 94-98 (2006); Mark, G. P., et al., Brain Res., 551: 308-310 (1991); and Rada, P., et al., Neuroscience, 134: 737-744 (2005)), while cessation of chronic intake of glucose precipitated a withdrawal-like decrease of dopamine release similar to that observed in morphine-dependent rats. See Colantuoni, C., et al., Obes. Res., 10: 478-488 (2002). Similarities between the neurochemical and behavioral consequences of excessive sugar consumption and addictive drugs lead to the concept of “sugar addiction”. See Avena, N. M., et al., Neurosci. Biobehav. Rev., (2007).
18-Methoxycoronaridine (18-MC), a potential anti-addictive agent and a selective antagonist of α3β4 nicotinic receptors, has been previously shown to attenuate sensitized morphine-induced dopamine release in the nucleus accumbens of morphine-experienced rats. Furthermore, systemic pretreatment with 18-MC has been shown to reduce the intravenous self-administration of morphine and other drugs (see Glick, S. D., et al., Brain Res., 719: 29-35 (1996) and Glick, S. D., et al., Neuroreport, 11: 2013-2015 (2000)) and alleviate several signs of acute opioid withdrawal in rats. See Rho, B., et al., Neuroreport, 9: 1283-1285 (1998). Given the significant role of dopamine in compulsive eating behavior and development of obesity, the current studies were undertaken to assess the effects of 18-MC on operant self-administration of sucrose, consumption of palatable fluids as well as weight gain of rats.
The present invention is directed to overcoming the deficiencies in the art.